Colonoscopic cancer detection rate: a new performance measure - is it FIT for purpose?

Introduction: Gastrointestinal symptoms correlate poorly with cancer diagnosis. A faecal immunochemical test (FIT) result of ≥10 µg has high sensitivity and negative predictive value for colorectal cancer (CRC) detection. An FIT-based diagnostic pathway may lead to more effective resource utilisation. We aimed to use National Endoscopy Database (NED) data to create a new colonoscopy performance measure, cancer detection rate (CDR) to assess the appropriate identification of target populations for colonoscopy; then to use CDR to assess the impact of implementing an FIT-based referral pathway locally. Methods: NED data were analysed to compare local diagnostic colonoscopic CDR in 2019 (prepathway revision) and 2021 (postpathway revision), benchmarked against overall national CDR for the same time frames. Results: 1, 123, 624 NED diagnostic colonoscopies were analysed. Locally, there was a significant increase in CDR between 2019 and 2021, from 3.01% (2.45%-3.47%) to 4.32% (3.69%-4.95%), p=0.003. The CDR increase was due to both a 10% increase in the number of CRCs detected and a 25% reduction in the number of diagnostic colonoscopies performed. Nationally, there was a smaller, but significant, increase in CDR from 2.02% (1.99%-2.07%) to 2.33% (2.29%-2.37%), p<0.001. The rate of increase in CDR% between 2019 and 2021 was significantly different locally compared with nationally. Conclusion: Our study indicates that the introduction of a robustly vetted FIT-based algorithm to determine whether diagnostic colonoscopy is required, is effective in increasing the colonoscopic CDR. Moreover, CDR appears to be a meaningful performance metric that can be automatically calculated through NED, enabling monitoring of the quality of referral and vetting pathways.

Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.

BACKGROUND: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification. METHODS: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing. FINDINGS: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses. INTERPRETATION: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome. FUNDING: Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Cardiac and perivascular myofibroblasts, matrifibrocytes, and immune fibrocytes in hypertension; commonalities and differences with other cardiovascular diseases.

Hypertension is a major cause of cardiovascular diseases such as myocardial infarction and stroke. Cardiovascular fibrosis occurs with hypertension and contributes to vascular resistance, aortic stiffness, and cardiac hypertrophy. However, the molecular mechanisms leading to fibroblast activation in hypertension remain largely unknown. There are two types of fibrosis: replacement fibrosis and reactive fibrosis. Replacement fibrosis occurs in response to the loss of viable tissue to form a scar. Reactive fibrosis occurs in response to an increase in mechanical and neurohormonal stress. Although both types of fibrosis are considered adaptive processes, they become maladaptive when the tissue loss is too large, or the stress persists. Myofibroblasts represent a subpopulation of activated fibroblasts that have gained contractile function to promote wound healing. Therefore, myofibroblasts are a critical cell type that promotes replacement fibrosis. Although myofibroblasts were recognized as the fibroblasts participating in reactive fibrosis, recent experimental evidence indicated there are distinct fibroblast populations in cardiovascular reactive fibrosis. Accordingly, we will discuss the updated definition of fibroblast subpopulations, the regulatory mechanisms, and their potential roles in cardiovascular pathophysiology utilizing new knowledge from various lineage tracing and single-cell RNA sequencing studies. Among the fibroblast subpopulations, we will highlight the novel roles of matrifibrocytes and immune fibrocytes in cardiovascular fibrosis including experimental models of hypertension, pressure overload, myocardial infarction, atherosclerosis, aortic aneurysm, and nephrosclerosis. Exploration into the molecular mechanisms involved in the differentiation and activation of those fibroblast subpopulations may lead to novel treatments for end-organ damage associated with hypertension and other cardiovascular diseases.

Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14+ monocytes and CD4+ and CD8+ T cells show disease-specific differences at the RNA level, epigenomic differences are only apparent upon multi-omics integration. The latter reveals enrichment at disease-associated loci in monocytes. We link putative functional SNPs to genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1, and show how disease-specific functional genomic data can be integrated with GWASs to enhance therapeutic target discovery. This study combines epigenetic and transcriptional analysis with GWASs to identify disease-relevant cell types and gene regulation of likely pathogenic relevance and prioritize drug targets.

Endoplasmic Reticulum Chemical Chaperone 3-Hydroxy-2-Naphthoic Acid Reduces Angiotensin II-Induced Vascular Remodeling and Hypertension In Vivo and Protein Synthesis In Vitro.

Background Investigations into alternative treatments for hypertension are necessary because current treatments cannot fully reduce the risk for the development of cardiovascular diseases. Chronic activation of unfolded protein response attributable to the endoplasmic reticulum stress has been proposed as a potential therapeutic target for hypertension and associated vascular remodeling. Triggered by the accumulation of misfolded proteins, chronic unfolded protein response leads to downstream signaling of cellular inflammation and dysfunction. Here, we have tested our hypothesis that a novel chemical chaperone, 3-hydroxy-2-naphthoic acid (3HNA) can attenuate angiotensin II (AngII)-induced vascular remodeling and hypertension. Methods and Results Mice were infused with AngII for 2 weeks to induce vascular remodeling and hypertension with or without 3HNA treatment. We found that injections of 3HNA prevented hypertension and increase in heart weight body weight ratio induced by AngII infusion. Histological assessment revealed that 3HNA treatment prevented vascular medial thickening as well as perivascular fibrosis in response to AngII infusion. In cultured vascular smooth muscle cells, 3HNA attenuated enhancement in protein synthesis induced by AngII. In vascular adventitial fibroblasts, 3HNA prevented induction of unfolded protein response markers. Conclusions We present evidence that a chemical chaperone 3HNA prevents vascular remodeling and hypertension in mice with AngII infusion, and 3HNA further prevents increase in protein synthesis in AngII-stimulated vascular smooth muscle cells. Using 3HNA may represent a novel therapy for hypertension with multiple benefits by preserving protein homeostasis under cardiovascular stress.

Effects of Rhododendron removal and prescribed fire on bees and plants in the southern Appalachians.

Rhododendron maximum is an evergreen shrub native to the Appalachian Mountains of North America that has expanded in recent decades due to past disturbances and land management. The purpose of this study was to explore how bees and plants were affected by the experimental removal of R. maximum followed by a prescribed fire in one watershed compared to a neighboring reference watershed. Bees and plants were sampled for three years in both watersheds. Comparisons were based on the rarefaction and extrapolation sampling curves of Hill numbers as well as multivariate methods to assess effects on community composition. Bee richness, Shannon's diversity, and Simpson's diversity did not differ between watersheds in the year after removal but were all significantly higher in the removal watershed in year two, following the prescribed fire. Bee Shannon's diversity and Simpson's diversity, but not richness, remained significantly higher in the removal watershed in the third year. Similar but weaker patterns were observed for plants. Comparisons of community composition found significant differences for bees in the second and third year and significant differences for plants in all three years. For both groups, significant indicator taxa were mostly associated with the removal watershed. Because bees appeared to respond more strongly to the prescribed fire than to the removal of R. maximum and these benefits weakened considerably one year after the fire, clearing R. maximum does not appear to dramatically improve pollinator habitat in the southern Appalachians. This conclusion is underscored by the fact that about one quarter of the bee species in our study area were observed visiting R. maximum flowers. The creation of open areas with wildflowers may be a better way to benefit bees in this region judging from the high diversity of bees captured in the small roadside clearings in this study.

Whole-genome sequencing reveals host factors underlying critical COVID-19.

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: To study human leukocyte antigen (HLA) allele associations in anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis. METHODS: A multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using χ2, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable. RESULTS: DRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, p < 10e-50) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, p = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (p = 0.003) and more frequently female (p = 0.015). Three patients with malignant thymomas did not carry DRB1*07:01, whereas patients with other tumors had high DRB1*07:01 frequency, suggesting that the presence of tumors other than thymomas may be coincidental and not causal. In both DRB1*07:01 heterozygous individuals and DRB1*07:01 negative subjects, DRB1*04:02 was associated with anti-LGI1 encephalitis, indicating an independent effect of this allele (OR = 6.85, p = 4.57 × 10-6 and OR = 8.93, p = 2.50 × 10-3, respectively). DRB1*04:02 was also independently associated with younger age at onset (ß = -6.68, p = 9.78 × 10-3). Major histocompatibility complex peptide-binding predictions using LGI1-derived peptides revealed divergent binding propensities for DRB1*04:02 and DRB1*07:01 alleles, suggesting independent pathogenic mechanisms. DISCUSSION: In addition to the established primary DRB1*07:01 association in anti-LGI1 encephalitis, we observe a secondary effect of DRB1*04:02 with lower age at onset. Our study provides evidence for secondary effects within HLA locus that correlate with clinical phenotypes in anti-LGI1 encephalitis.

Fine-Scale Genetic Structure in the United Arab Emirates Reflects Endogamous and Consanguineous Culture, Population History, and Geography.

The indigenous population of the United Arab Emirates (UAE) has a unique demographic and cultural history. Its tradition of endogamy and consanguinity is expected to produce genetic homogeneity and partitioning of gene pools while population movements and intercontinental trade are likely to have contributed to genetic diversity. Emiratis and neighboring populations of the Middle East have been underrepresented in the population genetics literature with few studies covering the broader genetic history of the Arabian Peninsula. Here, we genotyped 1,198 individuals from the seven Emirates using 1.7 million markers and by employing haplotype-based algorithms and admixture analyses, we reveal the fine-scale genetic structure of the Emirati population. Shared ancestry and gene flow with neighboring populations display their unique geographic position while increased intra- versus inter-Emirati kinship and sharing of uniparental haplogroups, reflect the endogamous and consanguineous cultural traditions of the Emirates and their tribes.

Glucose consumption of vascular cell types in culture: toward optimization of experimental conditions.

In this study, we have looked for an optimum media glucose concentration and compared glucose consumption in three vascular cell types, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and adventitial fibroblasts (AFs) with or without angiotensin II (AngII) stimulation. In a subconfluent 6-well experiment in 1 mL DMEM with a standard low (100 mg/dL), a standard high (450 mg/dL), or a mixed middle (275 mg/dL) glucose concentration, steady and significant glucose consumption was observed in all cell types. After 48-h incubation, media that contained low glucose was reduced to almost 0 mg/dL, media that contained high glucose remained significantly higher at ∼275 mg/dL, and media that contained middle glucose remained closer to physiological range. AngII treatment enhanced glucose consumption in AFs and VSMCs but not in ECs. Enhanced extracellular acidification rate by AngII was also observed in AFs. In AFs, AngII induction of target proteins at 48 h varied depending on the glucose concentration used. In low glucose media, induction of glucose regulatory protein 78 or hexokinase II was highest, whereas induction of VCAM-1 was lowest. Utilization of specific inhibitors further suggests essential roles of angiotensin II type-1 receptor and glycolysis in AngII-induced fibroblast activation. Overall, this study demonstrates a high risk of hypo- or hyperglycemic conditions when standard low or high glucose media is used with vascular cells. Moreover, these conditions may significantly alter experimental outcomes. Media glucose concentration should be monitored during any culture experiments and utilization of middle glucose media is recommended for all vascular cell types.

Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants.

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births [95% confidence interval (CI) 216-263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251-357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139-233), χ2 odds ratio = 1.7 (95% CI 1.3-2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations.

Contribution of ADAM17 and related ADAMs in cardiovascular diseases.

A disintegrin and metalloproteases (ADAMs) are key mediators of cell signaling by ectodomain shedding of various growth factors, cytokines, receptors and adhesion molecules at the cellular membrane. ADAMs regulate cell proliferation, cell growth, inflammation, and other regular cellular processes. ADAM17, the most extensively studied ADAM family member, is also known as tumor necrosis factor (TNF)-α converting enzyme (TACE). ADAMs-mediated shedding of cytokines such as TNF-α orchestrates immune system or inflammatory cascades and ADAMs-mediated shedding of growth factors causes cell growth or proliferation by transactivation of the growth factor receptors including epidermal growth factor receptor. Therefore, increased ADAMs-mediated shedding can induce inflammation, tissue remodeling and dysfunction associated with various cardiovascular diseases such as hypertension and atherosclerosis, and ADAMs can be a potential therapeutic target in these diseases. In this review, we focus on the role of ADAMs in cardiovascular pathophysiology and cardiovascular diseases. The main aim of this review is to stimulate new interest in this area by highlighting remarkable evidence.

Removing riparian Rhododendron maximum in post-Tsuga canadensis riparian forests does not degrade water quality in southern Appalachian streams.

In the past century, the evergreen woody shrub, Rhododendron maximum, has experienced habitat expansion following foundational tree species die-off in eastern US deciduous forests. Rhododendron can potentially alter stream chemistry, temperature, trophic dynamics, and in-stream decomposition rates, given its dominance in riparian areas. Here we conducted two operational-scale (3 ha) riparian treatments that removed rhododendron through cutting alone (CR, canopy removal), or removing both the rhododendron canopy and forest floor using cutting and prescribed fire (CFFR, canopy and forest floor removal). We expected that rhododendron shrub removal, with or without soil organic horizon removal, would increase soil nutrient availability and subsequently alter stream pH, acid neutralizing capacity (ANC), inorganic nitrogen (NO3-N, NH4-N), total dissolved inorganic nitrogen, dissolved organic carbon (DOC), calcium (Ca), potassium (K), and magnesium (Mg). We hypothesized that responses would occur more quickly in the CFFR treatment. Treatments reduced shrub-, but not tree basal area. Treatments lowered soil N, but not C. Stream chemistry responses to treatments varied between CR and CFFR and were transient, generally with pH, N, and some cations declining, and aluminum (Al) and DOC showing a pulse increase. By removing rhododendron, the remaining deciduous trees likely accelerated N uptake as soil moisture availability increased. This could partially explain why we observed lower than expected stream nutrients (NO3-N, Ca, and Mg) after treatments. Initial rhododendron slash on the forest floor coupled with incomplete consumption of the O-horizon on the CFFR treatment likely elevated DOC in the upper soil horizons and mobilized Al. From a management perspective, using these treatments to restore structure and function to riparian forests in the wake of eastern hemlock mortality, with or without fire, would most likely not result in short-term diminished water quality that is common when overstory trees are harvested and may even lower stream NO3-N concentrations long term.

Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.

Targeting Molecular Mechanism of Vascular Smooth Muscle Senescence Induced by Angiotensin II, A Potential Therapy via Senolytics and Senomorphics.

Cardiovascular disease (CVD) is a prevalent issue in the global aging population. Premature vascular aging such as elevated arterial stiffness appears to be a major risk factor for CVD. Vascular smooth muscle cells (VSMCs) are one of the essential parts of arterial pathology and prone to stress-induced senescence. The pervasiveness of senescent VSMCs in the vasculature increases with age and can be further expedited by various stressing events such as oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, and chronic inflammation. Angiotensin II (AngII) can induce many of these responses in VSMCs and is thus considered a key regulator of VSMC senescence associated with CVD. Understanding the precise mechanisms and consequences of senescent cell accumulation may uncover a new generation of therapies including senolytic and senomorphic compounds against CVD. Accordingly, in this review article, we discuss potential molecular mechanisms of VSMC senescence such as those induced by AngII and the therapeutic manipulations of senescence to control age-related CVD and associated conditions such as by senolytic.

78 kDa Glucose-Regulated Protein Attenuates Protein Aggregation and Monocyte Adhesion Induced by Angiotensin II in Vascular Cells.

Investigations of vascular smooth muscle cell (VSMC) phenotypic modulation due to angiotensin II (AngII) stimulation are important for understanding molecular mechanisms contributing to hypertension and associated vascular pathology. AngII induces endoplasmic reticulum (ER) stress in VSMCs, which has been implicated in hypertensive vascular remodeling. Under ER stress, 78 kDa glucose-regulated protein (GRP78) acts as an endogenous chaperone, as well as a master controller of unfolded protein response (UPR) to maintain protein quality control. However, the potential downstream consequences of ER stress induced by AngII on protein quality control and pro-inflammatory phenotype in VSMCs remain elusive. This study aims to identify protein aggregation as evidence of the disruption of protein quality control in VSMCs, and to test the hypothesis that preservation of proteostasis by overexpression of GRP78 can attenuate the AngII-induced pro-inflammatory phenotype in VSMCs. Increases in protein aggregation and enhanced UPR were observed in VSMCs exposed to AngII, which were mitigated by overexpression of GRP78. Moreover, GRP78 overexpression attenuated enhanced monocyte adhesion to VSMCs induced by AngII. Our results thus indicate that the prevention of protein aggregation can potentially mitigate an inflammatory phenotype in VSMCs, which may suggest an alternative therapy for the treatment of AngII-associated vascular disorders.

Mitochondrial Fission Mediates Endothelial Inflammation.

Endothelial inflammation and mitochondrial dysfunction have been implicated in cardiovascular diseases, yet, a unifying mechanism tying them together remains limited. Mitochondrial dysfunction is frequently associated with mitochondrial fission/fragmentation mediated by the GTPase Drp1 (dynamin-related protein 1). Nuclear factor (NF)-κB, a master regulator of inflammation, is implicated in endothelial dysfunction and resultant complications. Here, we explore a causal relationship between mitochondrial fission and NF-κB activation in endothelial inflammatory responses. In cultured endothelial cells, TNF-α (tumor necrosis factor-α) or lipopolysaccharide induces mitochondrial fragmentation. Inhibition of Drp1 activity or expression suppresses mitochondrial fission, NF-κB activation, vascular cell adhesion molecule-1 induction, and leukocyte adhesion induced by these proinflammatory factors. Moreover, attenuations of inflammatory leukocyte adhesion were observed in Drp1 heterodeficient mice as well as endothelial Drp1 silenced mice. Intriguingly, inhibition of the canonical NF-κB signaling suppresses endothelial mitochondrial fission. Mechanistically, NF-κB p65/RelA seems to mediate inflammatory mitochondrial fission in endothelial cells. In addition, the classical anti-inflammatory drug, salicylate, seems to maintain mitochondrial fission/fusion balance against TNF-α via inhibition of NF-κB. In conclusion, our results suggest a previously unknown mechanism whereby the canonical NF-κB cascade and a mitochondrial fission pathway interdependently regulate endothelial inflammation.

Involvement of Senescence and Mitochondrial Fission in Endothelial Cell Pro-Inflammatory Phenotype Induced by Angiotensin II.

Angiotensin II (AngII) has a crucial role in cardiovascular pathologies, including endothelial inflammation and premature vascular aging. However, the precise molecular mechanism underlying aging-related endothelial inflammation induced by AngII remains elusive. Here, we have tested a hypothesis in cultured rat aortic endothelial cells (ECs) that the removal of AngII-induced senescent cells, preservation of proteostasis, or inhibition of mitochondrial fission attenuates the pro-inflammatory EC phenotype. AngII stimulation in ECs resulted in cellular senescence assessed by senescence-associated ß galactosidase activity. The number of ß galactosidase-positive ECs induced by AngII was attenuated by treatment with a senolytic drug ABT737 or the chemical chaperone 4-phenylbutyrate. Monocyte adhesion assay revealed that the pro-inflammatory phenotype in ECs induced by AngII was alleviated by these treatments. AngII stimulation also increased mitochondrial fission in ECs, which was mitigated by mitochondrial division inhibitor-1. Pretreatment with mitochondrial division inhibitor-1 attenuated AngII-induced senescence and monocyte adhesion in ECs. These findings suggest that mitochondrial fission and endoplasmic reticulum stress have causative roles in endothelial senescence-associated inflammatory phenotype induced by AngII exposure, thus providing potential therapeutic targets in age-related cardiovascular diseases.

Cardiac Expression of Factor X Mediates Cardiac Hypertrophy and Fibrosis in Pressure Overload.

Activated factor X is a key component of the coagulation cascade, but whether it directly regulates pathological cardiac remodeling is unclear. In mice subjected to pressure overload stress, cardiac factor X mRNA expression and activity increased concurrently with cardiac hypertrophy, fibrosis, inflammation and diastolic dysfunction, and responses blocked with a low coagulation-independent dose of rivaroxaban. In vitro, neurohormone stressors increased activated factor X expression in both cardiac myocytes and fibroblasts, resulting in activated factor X-mediated activation of protease-activated receptors and pro-hypertrophic and -fibrotic responses, respectively. Thus, inhibition of cardiac-expressed activated factor X could provide an effective therapy for the prevention of adverse cardiac remodeling in hypertensive patients.

Elevated risk of invasive group A streptococcal disease and host genetic variation in the human leucocyte antigen locus.

Invasive group A streptococcal (GAS) disease is uncommon but carries a high case-fatality rate relative to other infectious diseases. Given the ubiquity of mild GAS infections, it remains unclear why healthy individuals will occasionally develop life-threatening infections, raising the possibility of host genetic predisposition. Here, we present the results of a case-control study including 43 invasive GAS cases and 1540 controls. Using HLA imputation and linear mixed models, we find each copy of the HLA-DQA1*01:03 allele associates with a twofold increased risk of disease (odds ratio 2.3, 95% confidence interval 1.3-4.4, P = 0.009), an association which persists with classical HLA typing of a subset of cases and analysis with an alternative large control dataset with validated HLA data. Moreover, we propose the association is driven by the allele itself rather than the background haplotype. Overall this finding provides impetus for further investigation of the immunogenetic basis of this devastating bacterial disease.